Sustained release drug delivery system suitable for oral administration

ABSTRACT

A single bead drug delivery system suitable for oral administration with multiply layered drug and polymer compartments can provide a two-step release of active agent to facilitate an immediate yet sustained drug delivery over a 24 hour period following oral administration with minimized variance between peak and trough levels of therapeutic drug amounts.

FIELD OF THE INVENTION

The present invention pertains to a drug delivery system suitable fororal administration that facilitates a two-step release of the activeagent. A key aspect of the present invention is the discovery that asingle orally administrable bead with multiply layered drug and polymercompartments can release the active agent in multiple phases to providean immediate yet sustained drug delivery over a 24 hour period.

BACKGROUND OF THE INVENTION

Drug efficacy generally depends upon the ability of the drug to reachits target in sufficient quantity to maintain therapeutic levels for thedesired time period. Orally administered drugs must overcome severalobstacles to reach their desired targets. Before orally administereddrugs enter the general circulation of the human body, they are absorbedinto the capillaries and veins of the upper gastrointestinal tract andare transported by the portal vein to the liver. The pH and enzymaticactivities found in gastrointestinal fluids may inactivate the drug orcause the drug to dissolve poorly. In addition, following theirabsorption in the intestine, orally administered drugs are often subjectto a "first pass" clearance by the liver and excreted into bile orconverted into pharmacologically inactive metabolites. Decreasedbioavailability of orally administered drugs is a consequence of thisfirst pass effect.

Orally administered drugs subject to the first pass effect generallyexhibit non-linear pharmacokinetics. Until the liver's metaboliccapacity has been exceeded, the amount of such drugs in the bloodstreamis significantly lower than the amount administered. This metabolicelimination of the given dose results in reduced bioavailability.However, once the administered dose exceeds the liver's metaboliccapacity, a significant increase in the drug concentration in thebloodstream may be obtained. The first pass phenomenon presentsparticular difficulties in the maintenance of therapeutic levels of anorally administered drug over an extended period such as 12 or 24 hours.

Drug delivery systems which have evolved with respect to orallyadministered drugs subject to the first pass effect include formulationscapable of immediate drug release that are suitable for administrationfrom 3-4 times daily, and formulations capable of immediate andsustained drug release that are suitable for once-daily administration.The second type of formulation is preferred because patient compliancewith prescribed drug regimens involving once-daily administration issubstantially higher than those involving multiple administrations. Asustained release formulation, however, may subject the patient to toxicdrug levels over part of the dosing period and sub-therapeutic druglevels over other portions of the dosing period, if the drug releasedoes not occur at appropriate time intervals. The maintenance oftherapeutic levels of an orally administered drug over an extendedperiod thus depends upon a drug delivery system capable of providing anappropriate release pattern.

Various drug delivery systems have been designed in attempts toameliorate the first pass effect. U.S. Pat. No. 5,439,689 describes onesuch system designed to deliver the calcium antagonist diltiazem in amanner to maintain the drug in the bloodstream in therapeutic druglevels throughout the 24 hour period following oral administration. Thisformulation accomplishes its dosing profile through the use of a blendof immediate drug release beads and delayed drug release beads. Onedisadvantage of this system is the relatively complicated manufacturingscheme. In contrast to a formulation comprising the blend of two typesof drug release beads, a single bead formulation could be manufacturedmore simply. A single bead formulation would not require the time andeffort required by the separate production of two types of drug releasebeads to prepare a final dosage form. Moreover, concerns regardingblending or double-filling homogeneity would be eliminated.

U.S. Pat. No. 4,894,240 describes an extended release drug deliverysystem in a single bead formulation. This system was also designed todeliver diltiazem in therapeutic drug levels over a 24 hour periodfollowing oral administration. However, subsequent tests demonstratedthat the commercial product based on this patent's teachings was unableto provide optimal diltiazem blood levels over the 24 hour periodfollowing oral administration because of significant variances betweenpeak and trough levels.

A valuable contribution to the art therefore would be the development ofa drug delivery system in a single bead formulation suitable for oraladministration that facilitates an immediate yet sustained release ofthe active agent over the 24 hour period following oral administrationwhile minimizing the variance between peak and trough levels.

SUMMARY OF THE INVENTION

Accordingly, an objective of the present invention is a single orallyadministrable bead with multiply layered drug and polymer compartmentsthat can release the active agent in multiple phases to provide animmediate yet sustained drug delivery over a 24 hour period with minimalvariance between peak and trough levels. Another objective of thepresent invention is the control of the lag time between the initial andsubsequent release of active agent. One other objective of the presentinvention is a comparative increase in active agent load (and thus drugdensity) above that achievable through a single bead formulation havinga single layer of active agent.

The present invention accomplishes these objectives through a drugdelivery system suitable for oral administration having a first drugcompartment containing an effective amount of an active agent, or apharmaceutically acceptable salt thereof, optionally in association withpharmaceutically acceptable binder(s) or excipient(s); a first polymercompartment which substantially envelops the first drug compartment toform a first drug/polymer interface; a second drug compartmentcontaining an effective amount of an active agent, or a pharmaceuticallyacceptable salt thereof, optionally in association with pharmaceuticallyacceptable binder(s) or excipient(s), where the second drug compartmentsubstantially envelops the first polymer compartment to form a seconddrug/polymer interface; and a second polymer compartment whichsubstantially envelops the second drug compartment to form a thirddrug/polymer interface.

The active agent contained in the second drug compartment facilitates aninitial release of active agent in an amount sufficient to achievetherapeutic levels at the appropriate target. The lag time and releaserate of active agent from the second drug compartment is predominantlycontrolled by the second polymer compartment, which is composed mainlyof one or more water insoluble polymers, one or more pH sensitive (i.e.,enteric) polymers, and/or one or more water soluble polymers.Accordingly, the character of the initial release phase may be alteredby changing the polymer composition of the second polymer compartment.

Upon exposure of the drug delivery system to higher pHs, a pH sensitivepolymer in the second polymer layer can dissolve. The dissolution of thepH sensitive polymer disrupts the polymer film and facilitates thecomplete release of the active agent from the second drug compartment.In turn, the first polymer compartment becomes exposed to thesurrounding medium.

The active agent contained in the first drug compartment provides thesustained release of active agent in an amount sufficient to maintaintherapeutic levels at the appropriate target throughout the 24 hourperiod following oral administration. When the second polymer and seconddrug compartments dissolve and/or detach from the drug delivery system,the first polymer compartment becomes exposed to the surrounding medium.The lag time and release rate of active agent from the first drugcompartment is predominantly controlled by the first polymercompartment, which is composed mainly of one or more water insolublepolymers, one or more pH sensitive (i.e., enteric) polymers, and/or oneor more water soluble polymers. Where a water soluble polymer isemployed, the dissolution of the first polymer compartment facilitatesthe release of the active agent from the first drug compartment.Accordingly, the character of the sustained release phase may be alteredby changing the polymer composition of the first polymer compartment.

DETAILED DESCRIPTION OF DRAWINGS

FIG. 1 is a schematic drawing depicting a typical bead containingmultiple layers of active drug and polymer materials. The release of theactive agent from the second drug compartment is predominantlycontrolled by the second polymer compartment and provides an immediaterelease of active agent in an amount sufficient to achieve therapeuticlevels at the appropriate target. The release of the active agent fromthe first drug compartment will likely occur after the dissolutionand/or detachment of the second drug and second polymer compartments. Insome instances, the release of active agent from the first drugcompartment is significantly delayed by the presence of the second drugand second polymer compartments. The release profile of active agentfrom the first drug compartment is predominantly controlled by the firstpolymer compartment. The active agent contained in the first drugcompartment provides the sustained release of active agent in an amountsufficient to maintain therapeutic levels at the appropriate targetthroughout the 24 hour period following oral administration.

FIG. 2 is a graph showing a typical in vitro drug release profile insimulated gastric fluid (SGF) (U.S. Pharmacopeia XXIII). Due to thepresence of pH sensitive polymers in the second polymer compartment, therelease of active agent from the first drug compartment is significantlyminimized in an acidic environment. Any release from the first drugcompartment in an acidic environment would likely result only fromdiffusion through both the first and second polymer compartments.Although the release of active agent from second drug compartmentexhibits some pH sensitivity, the ratio of pH sensitive polymers and pHindependent polymers in the second polymer compartment may be adjustedso that the release of active agent from the second drug compartment isindependent of pH change in the acidic range. FIG. 2 illustrates theimmediate release (e.g., approximately 40% of the total dose) of activeagent which occurs between 2 to 6 hours after immersion into thesimulated gastric fluid. The sustained release phase did not occurthroughout the 24 hour time period in simulated gastric fluid.

FIG. 3 is a graph showing a typical in vitro drug release profile insimulated intestinal fluid (SIF) (as described in U.S. PharmacopeiaXXIII with the exception of the absence of pancreatin). Due to the pHsensitive nature of the second polymer compartment, the release ofactive agent from the second drug compartment (e.g., approximately 40%of total dose) occurs almost immediately, and ends within four hours,after immersion into the simulated intestinal fluid. With thedissolution and/or detachment of the second drug and second polymercompartments, the first polymer compartment becomes exposed to thesimulated intestinal fluid. The first polymer compartment predominantlycontrols the release of active agent from the first drug compartment.FIG. 3 further illustrates that the sustained release phase (e.g.,approximately 60% of the total dose) occurs between 6 to 15 hours afterimmersion into the simulated intestinal fluid.

FIG. 4 is a graph showing a typical in vitro drug release profile usingan apparatus 3 assembly (U.S. Pharmacopeia XXIII) with a predeterminedmedium pH/time program. As such, test samples may be exposedsequentially to the following media for the specified time intervals:SGF (2 hours), pH 6 (1 hour), pH 6.5 (1 hour), pH 7 (1 hour), and SIF(19 hours). A stair-step release profile is depicted in this example,with the initial release phase and the subsequent release phase directedfrom the second drug compartment and the first drug compartment,respectively.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

The present invention relates to a drug delivery system representing asingle bead formulation suitable for oral administration that hasmultiple drug and polymer compartments which can release an active agentin multiple phases to provide an immediate yet sustained drug deliveryover a 24 hour period with minimal variance between peak and troughlevels.

The drug delivery system may also include a cosmetic coat compartmentwhich substantially envelops the second polymer compartment to form apolymer/cosmetic coat interface. A cosmetic coat compartment can providethe drug delivery system with a desired glossy appearance or color.

In another embodiment, the drug delivery system also has one or moreseal coat compartments. This seal coat compartment can exist at variouslocations of the drug delivery system, including the respectivedrug/polymer interfaces, the polymer/cosmetic coat interface, andsubstantially enveloping the second polymer compartment. In addition, aseal coat compartment may occur at multiple locations in the same drugdelivery system. A seal coat compartment located at the first and thirddrug/polymer interfaces can minimize the solvent penetration ormigration into the respective drug compartments during the coatingprocess. A seal coat compartment located at the second drug/polymerinterface or substantially enveloping the second polymer compartment canminimize the destruction or dissolution of the respective polymercompartments during production.

In one other embodiment, the first drug compartment substantiallyenvelops a inert core. The inert core, typically a starch or sugarsphere, is a manufacturing alternative. In the pharmaceutical arts,well-known "drug layering" techniques exist to bind active agent on tothe inert core (i.e., carrier) with an appropriate binding agent. Theinert core typically has a diameter ranging from approximately 18 to 45mesh and preferably within 35 to 40 mesh, if a high drug load isdesired. The active agent may be layered on to the inert core using aconventional coating pan, a fluidized particle coater, or arotogranulator.

In embodiments where an inert core is not employed, the first drugcompartment may be prepared by incorporating suitable ingredients suchas microcrystalline cellulose and the appropriate binders so that theactive agent can be wet granulated, extruded, and spherinized to formspherical beads as described in the art.

The final single bead formulations may be filled into hard gelatincapsules to the desired weight to facilitate delivery of sufficientquantities of active agent to achieve or maintain therapeutic levels atthe proper target. Final single bead formulations may also be applied tosoft gelatin capsules or tablet dosage forms with the addition of properexcipients. For pediatric applications, the beads may be dispersed intoa suitable liquid prior to administration.

The active agent of the present invention includes drugs that aresubject to the first pass effect, and their pharmaceutically acceptablesalts, pro-drug forms, metabolites, and derivatives. Various examples ofsuch drugs include acetaminophen, aldosterone, alprenolol,amitryptyline, aspirin, beclomethasone diproprionate, bromocriptine,butorphanol tartrate, chlormethiazole, chlorpheniramine, chlorpromazineHCl, cimetidine, codeine, cortisone, cyclobenzamine HCl,desmethylimipramine, dextropropoxyphene, dihydroergotamine, diltiazemHCl, dobutamine HCl, domperidone, dopamine HCl, doxepin HCl,epinephrine, ergoloid mesylates, ergotamine tartrate, estradiol,ethinylestradiol, flunisolide, fluorouracil, flurazepam HCl,5-fluoro-21-deoxyuridine, furosemide, glipizide, glyburide, glyceryltrinitrate, guanethidine sulfate, hydralazine HCl, imipramine HCl,indoramin, isoethorine HCl, isoethrine mesylate, isoprenaline,isoproterenol sulfate, isosorbide dinitrate, levallorphan tartrate,levodopa, lidocaine HCl, lignocaine, lorcainide, meperidine HCl,6-mercaptopurine, metaproterenol sulfate, methoxamine HCl,methylphenidate, methylprednisolone, methyltestosterone mesylate,metoclopramide, metoprolol tartrate, morphine sulfate, nalbuphine HCl,naloxone HCl, neostigmine, nifedipine, nitrendipine, nitroglycerin,norepinephrine bitartrate, norethindrone, nortriptylene HCl, oxprenolol,oxyphenbutazone, penicillamine, pentazocine HCl, pentazocine lactate,pentobarbital, petnidine, phenacetin, phentolamine HCl, phentolaminemesylate, phenylephrine HCl, phenylephrine bitartrate, phenytoin,pindolal, prazosin, prednisone, progesterone, propoxyphene HCl,propoxyphene napsylate, propranolol HCl, quinidine, reserpine, ritodrineHCl, salicylamide, salbutamol, secobarbital, testosterone, terbutaline,timolol maleate, tolbutamide, and verapamil HCl.

In a preferred embodiment of the present invention, the active agent isdiltiazem, or a pharmaceutically acceptable salt, diltiazem HCl. Afurther preferred embodiment is a drug delivery system containingdiltiazem, which exhibits the following in vitro dissolution profilewhen measured in a type 2 dissolution apparatus (paddle method)according to U.S. Pharmacopeia XXIII at 37° C. in simulated gastricfluid at 100 rpm: (a) from about 0% to about 40% of total diltiazem isreleased after 3 hours of measurement in said apparatus; (b) from about10% to about 50% of total diltiazem is released after 6 hours ofmeasurement in said apparatus; (c) and no more than about 60% of totaldiltiazem is released after 12 hours of measurement in said apparatus.

In another preferred embodiment, the diltiazem exhibits the following invitro dissolution profile when measured in a type 2 dissolutionapparatus (paddle) according to U.S. Pharmacopeia XXIII at 37° C. insimulated intestinal fluid at 100 rpm: (a) from about 20% to about 50%of total diltiazem is released after 3 hours of measurement in saidapparatus; (b) from about 20% to about 60% of total diltiazem isreleased after 6 hours of measurement in said apparatus; (c) from about35% to about 100% of total diltiazem is released after 12 hours ofmeasurement in said apparatus; (d) no less than about 70% of totaldiltiazem is released after 24 hours of measurement in said apparatus.

In yet another preferred embodiment is a drug delivery system containingdiltiazem, which exhibits the following in vitro dissolution profilewhen measured in a type 2 dissolution apparatus (paddle) according toU.S. Pharmacopeia XXIII at 37° C. in simulated gastric fluid at 100 rpm:(a) from about 0% to about 40% of total diltiazem is released after 3hours of measurement in said apparatus; (b) from about 10% to about 50%of total diltiazem is released after 6 hours of measurement in saidapparatus; (c) no more than about 60% of total diltiazem is releasedafter 12 hours of measurement in said apparatus; and also exhibits thefollowing in vitro dissolution profile when measured in a type 2dissolution apparatus (paddle) according to U.S. Pharmacopeia XXIII at37° C. in simulated intestinal fluid at 100 rpm: (a) from about 20% toabout 50% of total diltiazem is released after 3 hours of measurement insaid apparatus; (b) from about 20% to about 60% of total diltiazem isreleased after 6 hours of measurement in said apparatus; (c) from about35% to about 100% of total diltiazem is released after 12 hours ofmeasurement in said apparatus; (d) no less than about 70% of totaldiltiazem is released after 24 hours of measurement in said apparatus.

In one further embodiment, the amount of diltiazem contained in thefirst drug compartment and the amount of diltiazem contained in saidsecond drug compartment is present in a weight/weight ratio from 4:1 to1:4. Preferably, the amount of diltiazem contained in the first drugcompartment and the amount of diltiazem contained in said second drugcompartment is present in a weight/weight ratio of 3:2.

The first polymer compartment, or second polymer compartment, or bothfirst and second polymer compartments, of the drug delivery system maycontain suitable water insoluble polymers such as cellulose esters,cellulose ethers, and acrylic resins. Two examples of suitable acrylatepolymer for use in the second polymer compartment are Eudragit RL™ andEudragit RS™. With respect to the first polymer compartment, theacrylate polymers Eudragit RL™ and Eudragit RS™ are acceptable.

The first polymer compartment, or second polymer compartment, or bothfirst and second polymer compartments, of the drug delivery system maycontain suitable pH sensitive polymers such as hydroxypropylmethylcellulose phthalate, cellulose acetate phthalate, other celluloseethers or esters, and acrylic resins. Two examples of suitable acrylatepolymer for use in the second polymer compartment are Eudragit L™ andEudragit S™. With respect to the first polymer compartment, the acrylatepolymers Eudragit L™ and Eudragit S™ are acceptable.

The first polymer compartment, or second polymer compartment, or bothfirst and second polymer compartments, of the drug delivery system maycontain suitable water soluble polymers such as hydroxypropylmethylcellulose, hydroxypropyl cellulose, other cellulose ethers,polyvinyl alcohol, polyvinylpyrrolidone, polyethylene glycol, starch,and hydroxyethyl cellulose.

Other excipients which can facilitate the manufacturing operation orfinal film quality may be included. These excipients includeplasticizer, surfactant, hydrophobic anti-tackiness material, etc.

Without further elaboration, it is believed that one skilled in the artcan, using the preceding description, utilize the present invention tothe fullest extent. The following examples are illustrative only, andnot limiting of the remainder of the disclosure in any way whatsoever.

EXAMPLE ONE

An example of the composition of the first drug compartment is set forthin Table I.

                  TABLE I    ______________________________________    Ingredient      % w/w range                              % w/w example    ______________________________________    diltiazem hydrochloride                    70-100    90    binding agent(s)                    0-30      9    surfactant      0-10      1    ______________________________________

Either micronized or regular sized active raw material can be used toproduce the single bead formulations. Both the aqueous and the organicsolvent systems have been successfully evaluated and applied to thisinvention. Pharmaceutically acceptable solvents such as purified water,isopropyl alcohol, ethanol, etc., may be utilized. One or more bindingagents may be incorporated to bind the active diltiazem blend onto theinert core. Examples of suitable binding agents include hydroxypropylmethylcellulose, ethyl cellulose, polyvinylpyrrolidone, polymerizedacrylates, hydroxypropyl cellulose, hydroxyethyl cellulose, etc. Basedupon the binding agent selected, the ratio between diltiazem and bindingagent can vary widely.

The surfactant is employed, if necessary, to improve the texture of thedrug compartments and/or properties of the final dosage form. Otherpharmaceutical excipients such as glidant, anti-caking agent, lubricant,etc., may also be incorporated in the drug compartments to furtherimprove the properties of the final product as described in the art.

The first polymer compartment provides approximately 6 to 12 hours lagtime upon exposure to the surrounding medium before the sustainedrelease phase of diltiazem from the first drug compartment. The polymermaterials may include, but are not limited to, polymerized acrylates orcopolymers of acrylic and methacrylic acid esters or esters of eithermonomer (hereinafter polymerized acrylates), methacrylic acid and methylmethacrylate copolymer (hereinafter methacrylic acid copolymer). Thesepolymerized acrylates and methacrylic acid copolymers are commerciallyavailable from Rohm Tech Inc. under the tradenames Eudragit RS™,Eudragit RL™, Eudragit S™, and Eudragit L™. Other water insolublepolymers such as ethylcellulose, cellulose acetate,polydimethylsiloxane, etc., may also be employed to achieve the desiredrelease characteristics. Water soluble polymers may also be incorporatedin the polymer compartment. Examples of such polymers include, but arenot limited to, hydroxypropyl methylcellulose, hydroxypropyl cellulose,polyvinylpyrrolidone, etc. Other pharmaceutically acceptable ingredientsknown in the art, such as water soluble pore formers, plasticizers,anti-caking (or anti-adherent) agents, lubricants, separatingsubstances, anti-forming agents, surfactants, etc., may also beincorporated in the polymeric coating to achieve the desired propertiesor performance.

The first polymer compartment may be formed by various pharmaceuticalcoating technologies known in the art using suitable coating equipmentsuch as pan coaters, fluidized particle coaters, and rotogranulators.

An example of the first polymer compartment composition is shown below:

                  TABLE II    ______________________________________    Ingredient     % w/w range                             % w/w example    ______________________________________    Eudragit RS 100 ™                    0-45     28    Eudragit RL 100 ™                    0-30     5    Eudragit S 100 ™                    0-45     28    Eudragit L 100 ™                    0-30     5    Plasticizer     5-25     12    anti-caking agent                   10-55     22    ______________________________________

All the ingredients listed above may be dissolved or dispersed in thefollowing solvent system, whether used alone or in combination: purifiedwater, isopropyl alcohol, acetone, ethanol, etc. The weight of the drysolids applied to the first drug compartment may be in the range ofabout 20% to about 60% w/w, typically 40% w/w, of the total weight ofthe beads at this stage, i.e., the total weight of the inert core, ifany, and the first drug and first polymer compartments. A sufficientquantity of the polymeric mixture is required to envelop the active coreto ensure the desired lag time and release characteristics. The exactquantity may have to be adjusted carefully depending upon theformulation composition and the manufacturing processing conditions. Thesize of the first drug compartment dictates the bead surface area andtherefore affects the thickness of the first polymer compartment if afixed quantity of polymeric material is applied on to the first drugcompartment.

The second drug compartment may consist of a similar formulationcomposition as that of the first drug compartment, which Table Iillustrates. The ratio of diltiazem in the first drug compartment andthe second drug compartment may be in the range of 4:1 w/w to 1:4 w/w,preferably 3:2 w/w.

The second polymer compartment provides 0 to 4 hours lag time uponexposure to the surrounding medium before the immediate release phase ofdiltiazem from the second drug compartment. The polymer materials mayinclude, but are not limited to, polymerized acrylates or copolymers ofacrylic and methacrylic acid esters or esters of either monomer(hereinafter polymerized acrylates), methacrylic acid and methylmethacrylate copolymer (hereinafter methyacrylic acid copolymer). Thesepolymerized acrylates and methacrylic acid copolymers are commerciallyavailable from Rohm Tech Inc. under the tradenames Eudragit RS™,Eudragit RL™, Eudragit S™, and Eudragit L™. Enteric polymers whichdissolve in weakly acidic, neutral or slightly alkaline medium may beincorporated to ensure the breakage of the polymer coating and thusexpose the first polymer compartment when the dosage form reaches smallintestine and loses all the diltiazem in the second drug compartment.Other water insoluble polymers such as ethylcellulose, celluloseacetate, polydimethylsiloxane, etc., may also be employed to achieve thedesired release characteristics. Water soluble polymers may also beincorporated in the polymer coat. Examples of such polymers include, butare not limited to, hydroxypropyl methylcellulose, hydroxypropylcellulose, hydroxyethyl cellulose, polyvinylpyrrolidone, etc. Otherpharmaceutically acceptable ingredients known in the art, such as watersoluble pore formers, plasticizers, anti-caking (or anti-adherent)agents, lubricants, separating substances, anti-forming agents, etc.,may also be incorporated in the polymeric coating to achieve the desiredproperties or performance.

The second polymer compartment may be formed by various pharmaceuticalcoating technologies known in the art using suitable coating equipmentsuch as pan coaters, fluidized particle coaters, and rotogranulators.

An example of the second polymer compartment composition is shown below:

                  TABLE III    ______________________________________    Ingredient     % w/w range                             % w/w example    ______________________________________    Eudragit RS 100 ™                    0-30     10    Eudragit L 100 ™                    0-50     30    Plasticizer     5-25     10    anti-caking agent                   10-65     50    ______________________________________

All the ingredients listed above may be dissolved or dispersed in thefollowing solvent system, whether used alone or in combination: purifiedwater, isopropyl alcohol, acetone, ethanol, etc. The weight of the drysolids applied to the second drug compartment core may be in the rangeof about 5% to about 30% w/w, typically 16% w/w, of the total weight ofthe beads at this stage, i.e., the total weight of the inert core, ifany, the first drug and first polymer compartments, and the second drugand second polymer compartments.

An example of the in vitro dissolution profile of the drug deliverysystem containing diltiazem described above in a type 2 dissolutionapparatus (paddle) according to U.S. Pharmacopeia XXIII at 37° C. in0.1N HCl at 100 rpm is shown below:

                  TABLE IV    ______________________________________                % Released    Hours       (Preferred Range)    ______________________________________    3            0-40    6            0-50    24          25-60    ______________________________________

An example of the in vitro dissolution profile of the drug deliverysystem containing diltiazem described above in a type 2 dissolutionapparatus (paddle) according to U.S. Pharmacopeia XXIII at 37° C. insimulated gastric fluid (SGF) at 100 rpm is shown below:

                  TABLE V    ______________________________________                % Released    Hours       (Preferred Range)    ______________________________________    3            0-40    6            0-50    24          25-60    ______________________________________

An example of the in vitro dissolution profile of the drug deliverysystem containing diltiazem described above in a type 2 dissolutionapparatus (paddle) according to U.S. Pharmacopeia XXIII at 37° C. insimulated intestinal fluid (SIF) at 100 rpm is shown below:

                  TABLE VI    ______________________________________                % Released    Hours       (Preferred Range)    ______________________________________    3           20-50    6           20-60    12           35-100    24           70-100    ______________________________________

An example of the in vitro dissolution profile of the drug deliverysystem containing diltiazem described above in a type 3 bio-disk methodaccording to U.S. Pharmacopeia XXIII at 37° C. in a predeterminedpH/time program at 100 rpm is shown below. An example of thepredetermined pH/time program is as follows: SGF-2 hours; pH 6-1 hour;pH 6.5-1 hour; pH 7-1 hour; and SIF-19 hours.

                  TABLE VII    ______________________________________                % Released    Hours       (Preferred Range)    ______________________________________    3            0-40    6           20-60    12           30-100    24           80-100    ______________________________________

Those skilled in the art will find it apparent that variousmodifications and variations can be made to the formulations of thisinvention. Thus, the present invention is intended to cover suchmodifications and variations, provided they come within the scope of theappended claims and their equivalents.

The disclosure of all publications cited above are expresslyincorporated herein by reference in their entireties to the same extentas if each were incorporated by reference individually.

What is claimed is:
 1. A single bead drug delivery system suitable fororal administration comprising:a) a first drug compartment containing aneffective amount of an active agent, or a pharmaceutically acceptablesalt thereof, optionally in association with a pharmaceuticallyacceptable binder or excipient; b) a first polymer compartment whichsubstantially envelops said first drug compartment to form a firstdrug/polymer interface; c) a second drug compartment containing aneffective amount of an active agent, or a pharmaceutically acceptablesalt thereof, optionally in association with a pharmaceuticallyacceptable binder or excipient, wherein said second drug compartmentsubstantially envelops said first polymer compartment to form a seconddrug/polymer interface; d) a second polymer compartment whichsubstantially envelops said second drug compartment to form a thirddrug/polymer interface; and wherein said single bead drug deliverysystem can release said active agent in multiple phases.
 2. The drugdelivery system of claim 1, which further comprises:e) a cosmetic coatcompartment which substantially envelops said second polymer compartmentto form a polymer/cosmetic coat interface.
 3. The drug delivery systemof claim 1, which further comprises a seal coat compartment at saidfirst drug/polymer interface.
 4. The drug delivery system of claim 1,which further comprises a seal coat compartment at said seconddrug/polymer interface.
 5. The drug delivery system of claim 1, whichfurther comprises a seal coat compartment at said third drug/polymerinterface.
 6. The drug delivery system of claim 1, which furthercomprises a seal coat compartment that substantially envelops saidsecond polymer compartment.
 7. The drug delivery system of claim 2,which further comprises a seal coat compartment at said polymer/cosmeticcoat interface.
 8. The drug delivery system of claim 1, which furthercomprises a first seal coat compartment at said first drug/polymerinterface and a second seal coat compartment at said third drug/polymerinterface.
 9. The drug delivery system of claim 1, which furthercomprises a first seal coat compartment at said second drug/polymerinterface and a second seal coat compartment that substantially envelopssaid second polymer compartment.
 10. The drug delivery system of claim2, which further comprises a first seal coat compartment at said seconddrug/polymer interface and a second seal coat compartment at saidpolymer/cosmetic coat interface.
 11. The drug delivery system of claim1, wherein said first drug compartment substantially envelops an inertcore.
 12. The drug delivery system of claim 1, wherein said active agentis diltiazem, or a pharmaceutically acceptable salt thereof.
 13. Thedrug delivery system of claim 12, wherein said diltiazem exhibits thefollowing in vitro dissolution profile when measured in a type 2dissolution apparatus (paddle) according to U.S. Pharmacopeia XXIII at37° C. in simulated gastric fluid at 100 rpm:a) from about 0% to about40% of total diltiazem is released after 3 hours of measurement in saidapparatus; b) from about 10% to about 50% of total diltiazem is releasedafter 6 hours of measurement in said apparatus; and c) no more thanabout 60% of total diltiazem is released after 12 hours of measurementin said apparatus.
 14. The drug delivery system of claim 12, whereinsaid diltiazem exhibits the following in vitro dissolution profile whenmeasured in a type 2 dissolution apparatus (paddle) according to U.S.Pharmacopeia XXIII at 37° C. in simulated intestinal fluid at 100 rpm:a)from about 20% to about 50% of total diltiazem is released after 3 hoursof measurement in said apparatus; b) from about 20% to about 60% oftotal diltiazem is released after 6 hours of measurement in saidapparatus; c) from about 35% to about 100% of total diltiazem isreleased after 12 hours of measurement in said apparatus; and d) no lessthan about 70% of total diltiazem is released after 24 hours ofmeasurement in said apparatus.
 15. The drug delivery system of claim 12,wherein said diltiazem exhibits the following in vitro dissolutionprofile when measured in a type 2 dissolution apparatus (paddle)according to U.S. Pharmacopeia XXIII at 37° C. in simulated gastricfluid at 100 rpm:a) from about 0% to about 40% of total diltiazem isreleased after 3 hours of measurement in said apparatus; b) from about10% to about 50% of total diltiazem is released after 6 hours ofmeasurement in said apparatus; and c) no more than about 60% of totaldiltiazem is released after 12 hours of measurement in said apparatus;andwherein said diltiazem exhibits the following in vitro dissolutionprofile when measured in a type 2 dissolution apparatus (paddle)according to U.S. Pharmacopeia XXIII at 37° C. in simulated intestinalfluid at 100 rpm: a) from about 20% to about 50% of total diltiazem isreleased after 3 hours of measurement in said apparatus; b) from about20% to about 60% of total diltiazem is released after 6 hours ofmeasurement in said apparatus; c) from about 35% to about 100% of totaldiltiazem is released after 12 hours of measurement in said apparatus;and d) no less than about 70% of total diltiazem is released after 24hours of measurement in said apparatus.
 16. The drug delivery system ofclaim 12, wherein the amount of diltiazem contained in said first drugcompartment and the amount of diltiazem contained in said second drugcompartment is present in a weight/weight ratio from 4:1 to 1:4.
 17. Thedrug delivery system of claim 12, wherein the amount of diltiazemcontained in said first drug compartment and the amount of diltiazemcontained in said second drug compartment is present in a weight/weightratio of 3:2.
 18. The drug delivery system of claim 1, wherein saidfirst polymer compartment, or second polymer compartment, or both firstand second polymer compartments, contains one or more water insolublepolymer(s) selected from the group consisting of cellulose esters,cellulose ethers, and acrylic resins.
 19. The drug delivery system ofclaim 1, wherein said first polymer compartment, or second polymercompartment, or both first and second polymer compartments, contains oneor more pH sensitive polymer(s) selected from the group consisting ofhydroxypropyl methylcellulose phthalate, cellulose acetate phthalate,other cellulose ethers or esters, and acrylic resins.
 20. The drugdelivery system of claim 1, wherein said first polymer compartment, orsecond polymer compartment, or both first and second polymercompartments, contains one or more water soluble polymer(s) selectedfrom the group consisting of hydroxypropyl methylcellulose,hydroxypropyl cellulose, other cellulose ethers, polyvinyl alcohol,polyvinylpyrrolidone, polyethylene glycol, starch, and hydroxyethylcellulose.